The nucleic acids, ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), consist of long chains of alternating sugar and phosphate residues to each of which sugars is attached a nitrogenous base. The nitrogenous base is either a substituted purine or a substituted pyrimidine. Purine bases found in DNA and RNA include adenine, guanine, hypoxanthine, 1-methylhypoxanthine, 1-methylguanine and N.sup.2 -dimethylguanine. Pyrimidine bases found in nucleic acids include cytosine, thymine, uracil and 5-methylcytosine. The 5-carbon sugar derivatives of a purine or pyrimidine base are called nucleosides. For example, the nucleosides derived from cytosine include cytidine (cytosine plus ribose) and deoxycytidine (cytosine plus deoxyribose). A nucleoside with a phosphate group attached is called a nucleotide, for example, cytidine-3'-monophosphate (also known as 3'-cytidylic acid).
Both RNA and DNA are involved in the replication of viruses and in the growth of neoplasms. One of the more fruitful approaches to the therapy of viral disease or of neoplastic disease includes the use of drugs which are metabolic competitors (anti-metabolites) of naturally occurring nucleosides, nucleotides or nucleic acids. 5-Fluorouracil and 8-azaguanine are examples of such anti-metabolites. It is also possible to prepare anti-metabolites of the sugar portion of a nucleoside, as for example, the drug cytarabine which which is 1-.beta.-D-arabinofuranosylcytosine in which arabinose is substituted for the ribose of cytidine. Cytosine itself is 4-amino-2-oxo-1,2-dihydropyrimidine. In the naturally occurring nucleosides, cytosine would be attached through N.sup.1 to D-ribofuranoside, rather than D-arabinofuranoside as in cytarabine. Cytarabine (also known as cytosinearabinoside, arabinosylcytosine or ara-C) has been found to be active in several experimental tumors in animals and is presently used clinically for the treatment of acute leukemia. Resistance to the action of cytarabine occurs where the tumor or the surrounding tissue has high concentrations of cytidine deaminase, an enzyme which converts cytarabine to arabinosyluracil, an inactive compound.
It is an object of this invention to prepare a derivative of arabinofuranosylcytosine which is resistant to the action of cytidine deaminase.